Neurofibromatosis (NF) is a genetic disorder that affects the bone, soft tissue, skin and nervous system. It is classified into neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2), occurring in about 1 in 3,000 and 1 in 50,000 births, respectively. The disorders occur as a result of genetic defects, with NF1 resulting from a mutation on a gene located on chromosome 17 and NF2 on chromosome 22.
NF1, also known as von Recklinghausen Disease, is a hereditary disease seen in approximately 1 in 4,000 live births in the U.S. NF1 is characterized by a triad of café-au-lait spots (skin discolorations), cutaneous neurofibromata and iris Lisch nodules. Other features of the disorder may include skeletal dysplasia, vascular dysplasias, learning disabilities, seizures and other tumors of the neural crest origin, such as pheochromocytomas. In addition, about 10-15% of NF1 patients have low-grade astrocytomas, and less commonly, ependymoas or meningiomas.
NF2, is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss and balance dysfunction. Other findings include schwannomas of other cranial and peripheral nerves, meningiomas and juvenile posterior subcapsular contaract.
Both forms of NF are characterized by the growth of benign tumors called neurofibromas. These tumors can grow anywhere in the body where there are nerve cells. This includes nerves just under the surface of the skin, as well as nerves deeper within the body, spinal cord and/or brain. Neurofibromas usually originate in peripheral nerve fibres.
In NF1, neurofibromas most commonly grow on the skin or on the nerve to the eye. A tumor that grows on the nerve to the eye is called an optic glioma, and if it grows large enough can cause problems with vision, including blindness.
If untreated, a neurofibroma can cause severe nerve damage leading to loss of function to the area stimulated by that nerve, such as malformation of the long bones, curvature of the spine, short stature and growth hormone deficiency. Tumors on the optic nerve can cause visual loss, on the gastrointestinal tract may cause bleeding or obstruction, on the brain may lead to learning difficulties (speech problems), behavioural problems (learning disabilities or mental retaration), hearing problems, increased risk of epilepsy.
Currently, the only treatment available for NF is surgery.
The NF1 gene encodes neurofibromin, a tumor suppressor postulated to function in part as a Ras GTPase-activating protein. Ras is a downstream component of PDGFR and Kit receptors signalling, which have been found to be upregulated in NF1-positive cells.
As an inhibitor of both PDGFR and Kit receptor signalling, AMN107 has the potential to be of benefit in the treatment of NF.